This application claims priority under 35 U.S.C. 119 to Australian Patent No. 6074, filed Nov. 27, 1992.
This invention relates to a solution of paclitaxel having improved stability.
Paclitaxel is a compound extracted from the bark of a western yew, Taxus brevifolia and known for its antineoplastic activity. It is described for example in The Merck Index, Eleventh Edition 1989, monograph 9049.
In 1977, paclitaxel was chosen for development as an antineoplastic agent because of its unique mechanism of action and good cytotoxic activity against IP implanted D16 melanoma and the human X-1 mammary tumor xenograft. Paclitaxel is believed to function as a mitotic spindle poison and as a potent inhibitor of cell replication in vitro. Other mitotic spindle points (colchicine and podophyllotoxin) inhibit microtubule assembly. Paclitaxel employs a different mechanism of action since it appears to shift the equilibrium of polymerization/depolymerization toward polymer assembly and to stabilize microtubules against depolymerization under conditions which would cause rapid disaggregation of microtubules. The interference with the polymerization/depolymerization cycle in cells appears to interfere with both the replication and migration of cells.
After extensive preclinical screening in mouse tumor models, paclitaxel entered clinical trials in 1983. Over the past few years, paclitaxel has demonstrated good response rates in treating both ovarian and breast cancer patients who were not benefitting from vinca alkaloid or cisplatin therapy. It has also shown encouraging results in patients with other types of cancer including lung, melanoma, lymphoma, head and neck.
For further information, reference may be made to the U. S. National Cancer Institute""s Clinical Brochure for Taxol, revised July 1991, and papers presented at the Second National Cancer Institute Workshop on Taxol and Taxus held in Alexandria, Va. USA on Sep. 23-24, 1992.
It is a disadvantage of the known formulation that the paclitaxel therein degrades, with the result that the shelf life of the formulation is unsatisfactory, and there is therefore a need for a paclitaxel solution of improved stability.
Accordingly, in a general aspect the invention provides a solution containing paclitaxel, cremophor EL(trademark) and ethanol, characterized in that the pH of the solution has been adjusted into the range 1 to 8 by addition of an acid.
Acids in the form of powders, for example citric acid, are preferred over those which contain water, for example sulfuric acid. The most preferred acid for use in accordance with the present invention is citric acid, but a wide range of acids may be used including the following:
Citric acidxe2x80x94monohydrous
Citric acidxe2x80x94anhydrous
Citric acidxe2x80x94hydrous
Acetic acid
Formic acid
Ascorbic acid
Aspartic acid
Benzene sulphonic acid
Benzoic acid
Hydrochloric acid
Sulphuric acid
Phosphoric acid
Nitric acid
Tartaric acid
Diatrizoic acid
Glutamic acid
Lactic acid
Maleic acid
Succinic acid